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WO2017204163A1 - Médicament pour prévenir ou supprimer les lésions pulmonaires - Google Patents

Médicament pour prévenir ou supprimer les lésions pulmonaires Download PDF

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Publication number
WO2017204163A1
WO2017204163A1 PCT/JP2017/019036 JP2017019036W WO2017204163A1 WO 2017204163 A1 WO2017204163 A1 WO 2017204163A1 JP 2017019036 W JP2017019036 W JP 2017019036W WO 2017204163 A1 WO2017204163 A1 WO 2017204163A1
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Prior art keywords
amino
malonamide
naphthylsulfonyl
benzyl
diethyl
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English (en)
Japanese (ja)
Inventor
寒川　賢治
細田　洋司
崇 野尻
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National Cerebral and Cardiovascular Center
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National Cerebral and Cardiovascular Center
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a novel pharmaceutical composition for preventing or inhibiting lung injury, comprising a non-peptide angiotensin type 2 receptor (hereinafter referred to as AT2 receptor) agonist or a pharmacologically acceptable salt thereof as an active ingredient.
  • AT2 receptor non-peptide angiotensin type 2 receptor
  • the present invention also relates to a novel method for preventing or suppressing lung injury.
  • the human lung has a size of 6% of the body volume, is composed of a large number of small air sacs (alveoli), and controls gas exchange by the systemic circulation.
  • the alveoli are perfused with mixed venous blood through an extensive capillary network for gas exchange, and the alveolar membrane has a surface area greater than 100 m 2 and a thickness less than 1 ⁇ m.
  • the destruction of the alveolar membrane results in fluid leakage into the alveoli, resulting in a fatal loss of lung function.
  • Respiratory diseases are classified into interstitial pneumonia, chronic obstructive pulmonary disease (COPD), respiratory infection, allergic asthma, lung cancer, etc.
  • COPD chronic obstructive pulmonary disease
  • COPD are macrophages. It is a chronic inflammatory lung disease mainly composed of neutrophils.
  • Interstitial pneumonia is a pulmonary disease mainly composed of inflammatory lesions in the pulmonary interstitial tissue, and is divided into acute and chronic interstitial pneumonia in the clinical classification, acute interstitial pneunmonia (AIP) Suffered rapid respiratory failure and has a high fatality rate.
  • AIP acute interstitial pneunmonia
  • chronic interstitial pneumonia CIP is characterized by chronically progressing cough and respiratory failure, and is accompanied by progressive pulmonary fibrosis (PF).
  • PF pulmonary fibrosis
  • Some causative agent induces acute inflammation, and when this inflammation persists, the alveolar wall and alveoli are destroyed and transition to chronic inflammation. Later, in the process of repairing inflammation, excessive proliferation of connective tissue occurs and is thought to progress to pulmonary fibrosis.
  • This interstitial pneumonia is classified into secondary interstitial pneumonia with clear cause and idiopathic interstitial pneumonia with unclear cause. If the cause is clear, first remove the cause. Although improvement or progression can be suppressed, there is no established treatment for idiopathic interstitial pneumonia, and steroids and immunosuppressants are used from the viewpoint of temporarily suppressing inflammation.
  • COPD is characterized by obstructive arousal disorder induced by chronic bronchitis, emphysema or a combination of both, slowly progressing, irreversible, and a worldwide disease with high morbidity and mortality.
  • ARDS Acute Respiratory Distress Syndrome
  • angiotensinogen is converted into angiotensin I through renin, which is converted into angiotensin II (Ang II) having a strong and diverse physiological action by a converting enzyme such as angiotensin converting enzyme (ACE).
  • a converting enzyme such as angiotensin converting enzyme (ACE).
  • AT1 receptor Angiotensin type 1 receptor
  • AT2 receptor Angiotensin type 1 receptor
  • AT2 receptor As the function of AT2 receptor, it works by antagonizing AT1 receptor in many cells and tissues, mainly onset of pathological conditions such as hypotension, cell growth suppression, hypertrophy suppression, apoptosis promotion, extracellular matrix production inhibition, etc. It has been elucidated in recent years that it works in the direction of stopping progress.
  • the AT2 receptor is expressed at a high level in a wide range during fetal period, but its expression level decreases rapidly after birth.
  • pathological conditions such as vascular disorders and cardiovascular remodeling after myocardial infarction, it has become known that tissue-specific re-expression is important, and the importance of the AT2 receptor involved in preventing the onset and progression of various diseases Sex is attracting attention.
  • Target diseases include many disease groups involving the renin-angiotensin-aldosterone system, such as metabolic / circulatory diseases, and include cerebral infarction, kidney disease, heart disease, hypertension, diabetes, metabolic syndrome, etc. .
  • Non-patent Documents 2 and 3 Patent Documents 1 to 9
  • Each of these non-patent documents or compounds described in patent documents is characterized by a combination of a bisaryl structure and a sulfonamide group.
  • Malonic acid sulfonamide derivatives are also known as AT2 receptor agonists (Patent Document 10).
  • Non-patent Document 4 a peptide AT2 receptor agonist
  • the main object of the present invention is to provide a novel medicine for preventing or suppressing lung injury.
  • Another object of the present invention is to provide a novel method for preventing or suppressing lung injury.
  • non-peptide AT2 receptor ligands particularly non-peptide AT2 receptor agonists, can effectively prevent or suppress lung injury. Based on the knowledge, further studies have been made and the present invention has been completed.
  • the present invention relates to [1] a medicament for preventing or suppressing lung injury, which comprises a non-peptide angiotensin type 2 receptor agonist or a pharmacologically acceptable salt thereof as an active ingredient. .
  • the present invention also relates to [2] the medicament according to the above [1], wherein the lung injury is lung disease or acute respiratory distress induced by inflammation.
  • the present invention also relates to [3] The medicament according to [1] or [2], wherein the pulmonary disease induced by inflammation is pneumonia, pulmonary fibrosis resulting from chronic interstitial pneumonia, or chronic obstructive pulmonary disease. About.
  • the present invention provides [4] any one of [1] to [3], wherein the lung disorder is chronic interstitial pneumonia, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, or acute respiratory distress. It relates to the medicine.
  • the present invention also provides [5] non-peptidic AT2-type receptor agonist represented by the following general formula (I): [Wherein R 12 represents 2-naphthyl, trans- ⁇ -styryl, phenethyl, 3-phenoxypropyl, or 4-phenylbutyl; One of R 13 and R 14 represents a hydrogen atom, and the other one is isopropyl, isobutyl, neopentyl, allyl, —CH 2 —R 16 (wherein R 16 is an optionally substituted C 3-10 Cycloalkyl, optionally substituted heterocycle, or —CO—NR 5 R 6 (wherein R 5 and R 6 are the same or different, a hydrogen atom, C 1-6 alkyl, optionally substituted) Aryl or an optionally substituted heteroaryl, or R 5 and R 6 together with the nitrogen atom to which they are attached may form an optionally substituted cyclic amino).
  • R 12 represents 2-naphthyl, trans- ⁇ -s
  • R 16 ′ represents cyano or C 1-6 alkoxy
  • Ar 2 represents a substituted phenyl or an optionally substituted heteroaryl.
  • R 13 and R 14 together with the carbon atom to which they are attached, May form
  • R 15 is di (C 1-6 alkyl) amino or the following formula (In the formula, Z represents a hydrogen atom, a halogen atom or trifluoromethyl, Y represents a nitrogen atom or CH, and R 17 represents ethyl, isopropyl, or 3-pentyl.
  • the pharmaceutical according to any one of [1] to [4] above, which is a malonic acid sulfonamide derivative represented by the formula:
  • the present invention also provides [6] non-peptide angiotensin type 2 receptor agonist, N, N-diethyl-2- ⁇ 4-[(2,6-difluorobenzoyl) amino] benzyl ⁇ -N ′-(2-naphthylsulfonyl) malonamide, (2S) -2- [4- (Benzoylamino) benzyl] -N, N-diethyl-N ′-(2-naphthylsulfonyl) malonamide, (2S) -N, N-diethyl-2- ⁇ 4-[(2-fluorobenzoyl) amino] benzyl ⁇ -N ′-(2-naphthylsulfonyl
  • the present invention relates to [7] a pharmaceutical composition for preventing or inhibiting pulmonary disorders comprising a non-peptide AT2 receptor agonist or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention relates to a method for preventing or suppressing lung injury, comprising administering to a patient an effective amount of [8] a non-peptide AT2 receptor agonist or a pharmacologically acceptable salt thereof.
  • the present invention relates to [9] a non-peptide AT2 receptor agonist or a pharmacologically acceptable salt thereof for use in the prevention or suppression of lung injury.
  • the present invention relates to a prophylactic or inhibitory agent for lung injury comprising [10] a non-peptidic AT2 receptor agonist or a pharmacologically acceptable salt thereof.
  • the present invention relates to [11] use of a non-peptide AT2 receptor agonist or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or suppressing lung injury.
  • the present invention relates to [12] use of a non-peptide AT2 receptor agonist or a pharmaceutically acceptable salt thereof for preventing or suppressing lung injury.
  • the present invention relates to [13] a non-peptidic AT2 receptor agonist or a pharmacologically acceptable salt thereof and a combination drug with other drugs.
  • the other drug may be a prophylactic or inhibitory agent for pulmonary disorders other than the non-peptidic AT2 receptor agonist or a pharmacologically acceptable salt thereof.
  • the medicament of the present invention containing a non-peptidic angiotensin type 2 receptor agonist or a pharmacologically acceptable salt thereof as an active ingredient effectively prevents pulmonary disorders such as pulmonary diseases and acute respiratory distress induced by inflammation. It is characterized in that it can be prevented or suppressed. In addition, it is characterized in that lung administration can be prevented or suppressed by oral administration.
  • Pulmonary diseases induced by inflammation include pneumonia such as interstitial pneumonia (acute interstitial pneumonia, chronic interstitial pneumonia), chronic interstitial pneumonia (secondary chronic interstitial pneumonia, idiopathic chronic Chronic obstructive pulmonary disease induced by pulmonary fibrosis, chronic bronchitis, etc.
  • the medicament of the present invention can be used for interstitial pneumonia, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease. Diseases or acute respiratory distress can be particularly effectively prevented or suppressed.
  • the medicament of the present invention can effectively prevent or suppress pulmonary disorders in adults whose expression of angiotensin type 2 receptor has not been confirmed.
  • FIG. 1 is a diagram showing an experimental protocol in Examples 1 and 2.
  • FIG. 2 is a graph showing the results of the total number of cells in each group in Example 1.
  • FIG. 3 is a graph showing the results of the number of neutrophils in each group in Example 1.
  • FIG. 4 is a graph showing the results of the number of lymphocytes in each group in Example 1.
  • FIG. 5 is a graph showing the results of the total number of cells in each group in Example 2.
  • FIG. 6 is a graph showing the results of the neutrophil count of each group in Example 2.
  • FIG. 7 is a graph showing the results of the number of lymphocytes in each group in Example 2.
  • non-peptidic AT2 receptor agonist examples include compounds described in, for example, International Publication WO2008 / 156142, International Publication WO2002 / 096883, etc., and preferably described in International Publication WO2008 / 156142.
  • the following compound (I) is mentioned.
  • R 12 represents 2-naphthyl, trans- ⁇ -styryl, phenethyl, 3-phenoxypropyl, or 4-phenylbutyl;
  • One of R 13 and R 14 represents a hydrogen atom, and the other one is isopropyl, isobutyl, neopentyl, allyl, —CH 2 —R 16 (wherein R 16 is an optionally substituted C 3-10 Cycloalkyl, optionally substituted heterocycle, or —CO—NR 5 R 6 (wherein R 5 and R 6 are the same or different, a hydrogen atom, C 1-6 alkyl, optionally substituted) Aryl or an optionally substituted heteroaryl, or R 5 and R 6 together with the nitrogen atom to which they are attached may form an optionally substituted cyclic amino).
  • C 1-6 alkyl means a linear or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. , Pentyl, isopentyl, neopentyl, hexyl, isohexyl and the like.
  • C 2-6 alkenyl means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and having one or more carbon-carbon double bonds, such as vinyl, allyl 1-propenyl, isopropenyl, 2-butenyl, 1,3-butadienyl, 2-methyl-2-propenyl, prenyl, isopentenyl, 2-hexenyl and the like.
  • the C 2-6 alkynyl, a to 6 2 to carbon atoms, one or more carbon - means a linear or branched chain unsaturated hydrocarbon groups having carbon triple bond, e.g., ethynyl, 2- Examples include propynyl, 2-butynyl, 3-butynyl, 3-pentynyl, 5-hexynyl and the like.
  • C 1-6 alkoxy is synonymous with the above “C 1-6 alkyl”, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like.
  • C 3-10 cycloalkyl means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • the cycloalkyl is condensed with a benzene ring, and indane (for example, indan-1-yl, indan-2-yl, etc.), tetrahydronaphthalene (for example, tetrahydronaphthalen-5-yl, tetrahydronaphthalen-6-yl, etc.) Etc. may be formed.
  • C 3-10 cycloalkyl C 1-6 alkyl means a group in which the above “C 3-10 cycloalkyl” is substituted on the above “C 1-6 alkyl”.
  • the “C 1-6 alkyl” is preferably alkyl having 1 to 3 carbon atoms, such as cyclopropylmethyl, 2-cyclobutylethyl, 3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl. Etc.
  • Aryl preferably means an aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include phenyl and naphthyl.
  • the group includes ortho-fused bicyclic groups having 8 to 10 ring atoms and at least one ring being an aromatic ring (for example, indenyl).
  • Aryl C 1-6 alkyl means a group in which the above “C 1-6 alkyl” is substituted with the above “aryl”, such as benzyl, benzohydryl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenyl. Butyl, 5-phenylpentyl, 6-phenylhexyl, 1-naphthylmethyl, 2-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, 3- (2-naphthyl) propyl, 4 -(2-naphthyl) butyl and the like.
  • aryl such as benzyl, benzohydryl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenyl. Butyl, 5-phenylpentyl, 6-phenylhexyl,
  • the aryl C 2-6 alkenyl means a group in which the above “C 2-6 alkenyl” is substituted with the above “aryl”.
  • the “C 2-6 alkenyl” is preferably alkenyl having 2 to 4 carbon atoms, such as trans- ⁇ -styryl, cinnamyl, 3- (1-naphthyl) -2-propenyl, 3- (2-naphthyl). -2-propenyl and the like.
  • Heteroaryl means an aromatic group containing one or more (preferably 1 to 4) heteroatoms selected from an oxygen atom, a sulfur atom and / or a nitrogen atom in addition to a carbon atom.
  • These groups include 5- or 6-membered monocyclic groups, or ortho-fused bicyclic groups having 8 to 10 ring atoms derived therefrom (especially benzo derivatives), and propenylene, trimethylene or tetramethylene As well as its stable N-oxide and the like.
  • Examples of the group include pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4 -Oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1, 3,5-triazinyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, oxazolopyridyl, imidazopyridazin
  • the heteroaryl C 1-6 alkyl means a group obtained by substituting the above “C 1-6 alkyl” with the above “heteroaryl”.
  • the “C 1-6 alkyl” is preferably alkyl having 1 to 5 carbon atoms, such as 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (2-pyridyl) ethyl, 2- ( 3-pyridyl) ethyl, 2- (4-pyridyl) ethyl, 3- (2-pyridyl) propyl, 3- (3-pyridyl) propyl, 3- (4-pyridyl) propyl, 2-thienylmethyl, 3-thienyl Methyl, 2- (2-thienyl) ethyl, 3- (2-thienyl) propyl, 4-pyrazolylmethyl, 2- (4-pyrazolyl) ethyl, 3- (4-pyrazolyl) propyl, 2-thiazoly
  • the heterocycle means a cyclic hydrocarbon group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and / or a sulfur atom.
  • the group is non-aromatic and may be saturated or partially unsaturated.
  • the group includes not only a single ring but also a spiro ring, and a 4- to 7-membered monocyclic group or a 10- or 11-membered spiro ring group is preferable.
  • Examples of the group include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, 1,4-diazepanyl, 1,2,5,6-tetrahydropyridyl, tetrahydropyranyl, cyclopentanespiro-4′-piperidinyl and the like.
  • the heterocycle may be condensed with an aromatic ring. Examples of the condensed ring include indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, spiro [indan-1,4′-piperidine] -1 '-Ill and the like.
  • Cyclic amino means a cyclic hydrocarbon group containing at least one nitrogen atom, in which the nitrogen atom is a bond of the group.
  • the ring may contain 1 to 3 of the same or different heteroatoms selected from, for example, a further nitrogen atom, oxygen atom and sulfur atom.
  • the group is non-aromatic and may be saturated or partially unsaturated.
  • the group includes not only a single ring but also a spiro ring, and a 4- to 7-membered monocyclic group or a 10- or 11-membered spiro ring group is preferable.
  • Examples of the group include azetidino, pyrrolidino, piperidino, piperazino, morpholino, 1,4-diazepan-1-yl, 1,2,5,6-tetrahydropyridino, tetrahydroimidazolino, cyclopentanespiro-4′-piperidino Etc.
  • the cyclic amino may be condensed with an aromatic ring. Examples of the condensed ring include indolino, isoindolino, 1,2,3,4-tetrahydroquinolino, 1,2,3,4-tetrahydroisoquinolino, spiro [indan-1,4′-piperidine] -1 '-Ill and the like.
  • halogen atom examples include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom.
  • Optionally substituted C 3-10 cycloalkyl “optionally substituted heterocycle”, “optionally substituted aryl”, “optionally substituted heteroaryl” and “substituted Examples of the substituent in “optionally cyclic amino” include 1 to 3 substituents selected from the substituent group A shown below. In the case of a plurality of substituents, they may be the same or different.
  • Substituent group A halogen atom (as defined above), hydroxyl group, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl (as defined above), C 2-6 alkenyl (as defined above), C 2-6 alkynyl (as defined above), C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 3-10 cycloalkyl (as defined above), C 3-10 cycloalkyl C 1- 6 alkyl (as defined above), aryl (as defined above), aryloxy, aryl C 1-6 alkyl (as defined above), aryl C 2-6 alkenyl (as defined above), aryl C 2-6 alkynyl, hetero Aryl (as defined above), heteroaryloxy, heteroaryl C 1-6 alkyl (as defined above), heterocycle (as defined above), oxo, —COOR a ,
  • Substituent group B halogen atom (as defined above), hydroxyl group, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl (as defined above), C 2-6 alkenyl (as defined above), C 2-6 alkynyl (as defined above), C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 3-10 cycloalkyl (as defined above), C 3-10 cycloalkyl C 1- 6 alkyl (as defined above), aryl (as defined above), aryloxy, aryl C 1-6 alkyl (as defined above), aryl C 2-6 alkenyl (as defined above), aryl C 2-6 alkynyl, hetero Aryl (as defined above), heteroaryloxy, heteroaryl C 1-6 alkyl (as defined above), heterocycle (as defined above), oxo, —COOR a ,
  • C 1-6 alkyl part of C 1-6 alkoxy has the same meaning as the above “C 1-6 alkyl”, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy. Etc.
  • C 1-6 alkyl part of C 1-6 alkylthio has the same meaning as the above “C 1-6 alkyl”, and examples thereof include methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio and the like.
  • C 1-6 alkyl portion of the C 1-6 alkylsulfinyl has the same meaning as the above-mentioned "C 1-6 alkyl", for example, methylsulfinyl, ethylsulfinyl, propyl sulfinyl, isopropyl sulfinyl, butylsulfinyl, pentylsulfamoyl alkylsulfonyl, And hexylsulfinyl.
  • aryl part of aryloxy has the same meaning as the above “aryl”, and examples thereof include phenoxy, 1-naphthoxy, 2-naphthoxy and the like.
  • Aryl C 2-6 alkynyl means a group in which the above “C 2-6 alkynyl” is substituted with the above “aryl”.
  • the “C 2-6 alkynyl” is preferably alkynyl having 2 to 4 carbon atoms, and examples thereof include phenylethynyl.
  • heteroaryl part of heteroaryloxy has the same meaning as the above “heteroaryl”, and examples thereof include 2-pyridyloxy, 2-benzothiazolyloxy and the like.
  • R a to R j are each a hydrogen atom, C 1-6 alkyl (as defined above), aryl (as defined above), aryl C 1-6 alkyl (as defined above), heteroaryl (as defined above) Or a heteroaryl C 1-6 alkyl (as defined above), and these groups may further have 1 to 3 substituents selected from Substituent Group A at substitutable positions. Good.
  • R b and R c , R e and R f , R i and R j in -NR b R c , -NR e R f , -NR i R j , and cyclic nitrogen may further have 1 to 3 substituents selected from Substituent Group A at substitutable positions.
  • the cyclic amino formed by -NR e R f is a cyclic amino having oxo (for example, 2-pyrrolidinon-1-yl, 1-oxoisoindoline-2-yl, succinimide, oxazolidine-2-one-3-yl, 2-benzoxazolinon-3-yl, phthalimide, 4-quinazolinon-3-yl, etc.).
  • oxo for example, 2-pyrrolidinon-1-yl, 1-oxoisoindoline-2-yl, succinimide, oxazolidine-2-one-3-yl, 2-benzoxazolinon-3-yl, phthalimide, 4-quinazolinon-3-yl, etc.
  • T 1 to T 3 are each C 1-6 alkyl (as defined above), C 2-6 alkenyl (as defined above), C 2-6 alkynyl (as defined above), C 3-10 cycloalkyl (as defined above) synonymous), C 3-10 cycloalkyl C 1-6 alkyl (as defined above), aryl (as defined above), aryl C 1-6 alkyl (as defined above), heteroaryl (as defined above), heteroaryl C 1-6 alkyl (as defined above), cyclic amino (as defined above), or heterocycle (as defined above), and these groups are further substituted with 1 to 3 substituents selected from substituent group A
  • substituent group A For example, as aryl or heteroaryl having 1 to 3 substituents selected from substituent group A, 2-aminophenyl, 2-amino-5- Fluorophenyl, 2-amino-6-fluorophenyl, 2-fluorophenyl, 4-methoxy And phenyl,
  • Example compounds 1 to 588 described in International Publication WO2008 / 156142 are particularly preferable.
  • MeO represents a methoxy group
  • ph represents a phenyl group
  • TFA represents trifluoroacetic acid
  • non-peptidic AT2 receptor agonist in the active ingredient of the present invention, the following compounds or pharmacologically acceptable salts thereof are particularly preferable.
  • Examples of the pharmacologically acceptable salt of the non-peptide AT2 receptor agonist of the present invention include inorganic acid addition salts (for example, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.) Organic acid addition salts (e.g.
  • the non-peptidic AT2 receptor agonist or pharmacologically acceptable salt thereof used in the present invention may exhibit polymorphism, and if it contains an asymmetric carbon in the molecule, it is an optical isomer.
  • Stereoisomers can exist.
  • this invention includes a hydrate and a solvate.
  • it can exist as more than one tautomer depending on the presence of an unsaturated bond, the type of substituent, pH and the like. Accordingly, the present invention includes any stereoisomer, optical isomer, polymorph, tautomer, and any mixture thereof as described above.
  • the non-peptidic AT2 receptor agonist or pharmacologically acceptable salt thereof used in the present invention can be produced by a known method, for example, the general formula (I) or a pharmacologically acceptable salt thereof. Can be produced by the method described in International Publication WO2008 / 156142.
  • the medicament of the present invention only needs to contain the above-mentioned non-peptidic AT2 receptor agonist or a pharmacologically acceptable salt thereof as an active ingredient, but there are known pharmacologically acceptable non-active ingredients other than the active ingredient.
  • Active carriers, excipients, diluent stabilizers, surfactants, lubricants, buffers, sweeteners, flavoring agents, binders, antioxidants, coating agents, flavoring agents, fragrances, sugar coatings , Additives such as tonicity agents, emulsifiers, thickening agents, pH adjusters, dispersants, disintegrating agents, preservatives, preservatives, solubilizing agents, and the like may be included.
  • the dosage of the medicament of the present invention varies depending on the type of disease, the age of an individual (patient), the body weight, the degree of symptoms, and the administration route, and can be appropriately set according to the purpose of administration.
  • the dose for oral administration to an adult is 0.01 to 1000 mg / kg body weight / day, more preferably 0.05 to 500 mg / kg body weight / day, as a non-peptide AT2 receptor agonist,
  • the set dose is preferably administered once to several times a day.
  • the dosage form and administration route of the medicament of the present invention comprising a non-peptidic AT2 receptor agonist or a pharmacologically acceptable salt thereof as an active ingredient is not particularly limited, and one or two or more kinds are selected according to the patient's situation.
  • Oral or parenteral agents can be selected.
  • oral dosage forms include tablets, capsules, granules, pills, powders, tablets for oral use, oral solutions, emulsions, suspensions, syrups, jelly-forms, wrinkles, gummi-forms, and pastes. And the like.
  • parenteral forms include solid preparations, liquid preparations, spray preparations, inhalants, ointments, cream preparations, gel preparations, patches and the like. These preparations are produced by a known method or a method known per se.
  • the lung disorder refers to pneumonia, pulmonary fibrosis resulting from chronic interstitial pneumonia, lung disease induced by inflammation such as chronic obstructive pulmonary disease (COPD); acute respiratory distress (Acute Respiratory® Distress® Syndrome, ARDS), etc.
  • pulmonary disorders include acute interstitial pneumonia (AIP), chronic interstitial pneumonia (CIP), secondary interstitial pneumonia, idiopathic interstitial pneumonia, etc. Interstitial pneumonia; idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; acute respiratory distress; respiratory infection; allergic asthma; lung cancer;
  • the present invention includes a pharmaceutical composition for preventing or suppressing lung injury comprising a non-peptidic AT2 receptor agonist or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention includes a method for preventing or suppressing lung injury, comprising administering to a patient an effective amount of a non-peptide AT2 receptor agonist or a pharmacologically acceptable salt thereof.
  • the present invention includes a non-peptidic AT2 receptor agonist or a pharmaceutically acceptable salt thereof for use in preventing or suppressing lung injury.
  • the present invention includes a prophylactic or suppressive agent for lung injury containing a non-peptidic AT2 receptor agonist or a pharmacologically acceptable salt thereof.
  • the present invention includes the use of a non-peptide AT2 receptor agonist or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or suppressing lung injury.
  • the present invention encompasses the use of a non-peptidic AT2 receptor agonist or a pharmaceutically acceptable salt thereof for preventing or inhibiting lung injury.
  • the present invention includes a non-peptide AT2 receptor agonist or a pharmacologically acceptable salt thereof used for prevention or suppression of lung injury.
  • the present invention encompasses a non-peptidic AT2 receptor agonist or a pharmacologically acceptable salt thereof and a combination drug with other drugs. Examples of other drugs include steroids and immunosuppressants.
  • LPS Lipopolysaccharide
  • E. coli 055-derived Wood-based flame retardant
  • methylcellulose water Wood-based solvent
  • Wako Pure Chemical Industries, Ltd. methylcellulose water
  • (2S) -2- [4- (benzoylamino) benzyl] -N, N-diethyl-N ′-(2-naphthylsulfonyl) malonamide is used as compound C, and N- (4-fluoro Phenyl) -2-isobutyl-N-isopropyl-N ′-((E) -styrylsulfonyl) malonamide was used.
  • Oropharyngeal aspiration method De Vooght V, Vanoirbeek JA, Haenen S, Verbeken E, Nemery B, Hoet PH. Oropharyngeal aspiration: An alternative route for challenging in a mouse model of chemical-induced asthma. Toxicology. 2009; see 259: 84-9) Caused inflammation.
  • a non-inflammatory-inducing control group 50 ⁇ l of physiological saline was similarly administered intratracheally to another group in which only the solvent was freely ingested for 4 days (physiological saline administration group).
  • physiological saline administration group 50 ⁇ l of physiological saline was similarly administered intratracheally to another group in which only the solvent was freely ingested for 4 days.
  • All mice were euthanized, and 1 ml of Cold PBS was forcibly injected into the lungs from the trachea of the mice using a 1 ml syringe, and the whole volume was collected three times.
  • a non-peptide angiotensin type 2 receptor agonist such as Compound A or a pharmacologically acceptable salt thereof has an effect of suppressing inflammation in bronchi and lung, and lung disease induced by inflammation. It is considered effective for the prevention and / or treatment of lung disorders such as
  • Example 2 Anti-inflammatory action of compound C in LPS-induced lung injury model
  • the experimental protocol is shown in FIG.
  • Six-week-old male C57BL / 6N mice (Japan SLC) were allowed to freely take an aqueous solution in which Compound C was dissolved at a concentration of 0.2 mg / mL using a 0.5% methylcellulose solution as a solvent (Compound C administration group).
  • Compound C administration group On the other hand, only the solvent was freely ingested for 4 days in the control group (Vehicle administration group).
  • a non-inflammatory-inducing control group 50 ⁇ l of physiological saline was similarly administered intratracheally to another group in which only the solvent was freely ingested for 4 days (physiological saline administration group).
  • physiological saline administration group 50 ⁇ l of physiological saline was similarly administered intratracheally to another group in which only the solvent was freely ingested for 4 days.
  • All mice were euthanized, and 1 ml of Cold PBS was forcibly injected into the lungs from the trachea of the mice using a 1 ml syringe, and the whole volume was collected three times.
  • a non-peptide angiotensin type 2 receptor agonist such as Compound C or a pharmacologically acceptable salt thereof has an effect of suppressing inflammation in bronchi and lung, and lung disease induced by inflammation. It is considered effective for the prevention and / or treatment of lung disorders such as
  • the present invention is an excellent drug capable of preventing or suppressing lung injury, and is useful in the medical field and the like.

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Abstract

L'invention porte sur un médicament contenant un agoniste du récepteur de l'angiotensine II, ou un sel comparable, utilisé comme agent actif pour traiter, ou prévenir les lésions pulmonaires.
PCT/JP2017/019036 2016-05-23 2017-05-22 Médicament pour prévenir ou supprimer les lésions pulmonaires Ceased WO2017204163A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008535900A (ja) * 2005-04-12 2008-09-04 ヴィコール・ファルマ・アーベー 新規な二環式アンジオテンシンｉｉアゴニスト
WO2008156142A1 (fr) * 2007-06-20 2008-12-24 Mitsubishi Tanabe Pharma Corporation Nouveau dérivé sulfamide d'acide malonique et son usage pharmaceutique
WO2015152393A1 (fr) * 2014-04-03 2015-10-08 国立研究開発法人国立循環器病研究センター Médicament pour inhibition de métastase de tumeur maline
WO2016139475A1 (fr) * 2015-03-02 2016-09-09 Vicore Pharma Ab Agoniste du récepteur de l'angiotensine ii pour le traitement de la fibrose pulmonaire

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008535900A (ja) * 2005-04-12 2008-09-04 ヴィコール・ファルマ・アーベー 新規な二環式アンジオテンシンｉｉアゴニスト
WO2008156142A1 (fr) * 2007-06-20 2008-12-24 Mitsubishi Tanabe Pharma Corporation Nouveau dérivé sulfamide d'acide malonique et son usage pharmaceutique
WO2015152393A1 (fr) * 2014-04-03 2015-10-08 国立研究開発法人国立循環器病研究センター Médicament pour inhibition de métastase de tumeur maline
WO2016139475A1 (fr) * 2015-03-02 2016-09-09 Vicore Pharma Ab Agoniste du récepteur de l'angiotensine ii pour le traitement de la fibrose pulmonaire

Non-Patent Citations (3)

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Title
BRUCE E ET AL.: "Selective actibation of angiotensin AT 2 receptors attenuates progression of plumonary hypertension and inhibits cardiopulmonary fibrosis", BRITISH JOURNAL OF PHARMACOLOGY, vol. 172, 2015, pages 2219 - 2231, XP055276760 *
MATHESON MC ET AL.: "Associateion of IL 8,CXCR2 and TNF-a polymorphisms and airway disease", J HUM GENET, vol. 51, 2006, pages 196 - 203, XP019374367 *
NURCING TODAY, vol. 24, no. 7, 2009, pages 60 - 62 *

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